How do early and lifelong exposure to dietary AGEs affect tissue, gut sensitivity, and microbiota in mice?

Introduction:Diet plays a crucial role in triggering deleterious physiological responses. Dietary Advanced glycation end-products(dAGEs) are suggested to lead to chronic low-grade inflammation (CLGI), oxidative stress, and alter gut bacteria.Studies investigate how glycation products like dietary carboxymethyl-lysine (dCML) and the Receptor for AdvancedGlycation End-Products (RAGE) affect cellular responses, but it is unclear if early-life or lifelong exposure to dAGEscould contribute cited consequences of AGE intake, and whether these effects can be reversed.Materials and methods:Our study employed standard and an in-house prepared protein-dCML model to enrich mice food and explored how ahigh (13-times) dCML-enriched diet affects Wild-Type (WT) and RAGE KO mice from birth to 6, 35, and 70 weeks. Wealso investigated if switching to a standard diet at 6-weeks of age could reverse the potential dCML effects in the“Switch group”. We assessed outcomes at systemic and local levels using quantitative (LC-MS/MS) and molecularbiology methods (qRT-PCR, Metagenomics) to quantify dCML and physiological changes, respectively, in multipleorgans.Results:We confirmed the accumulation of free dCML in kidneys (3x), ileum (17x), and colon (20x) from 6 to 70 weeks of diet,regardless of RAGE expression. Switching diets lowered dCML comparable control conditions. The dCML-enrich dietdid not notably affect endogenous glycation, inflammation, or senescence. TNFα, VCAM1, IL6, and P16 geneexpression roughly doubled with age, especially in WT kidneys. There were notable increases in TNFα expressiondetected in the intestinal tract of the Switch group, suggesting an increased inflammatory reaction that could be relatedto timing of dietary shifts. Minor alterations in gut microbiota communities were observed.Discussion and conclusion:While persistent intake of dCML resulted in increased free dCML levels within tissues, there were no notable increasesin parameters associated with inflammageing, oxidative stress, or significative microbial community shifts. However,early-life diet switching seemed to contribute with greater sensitivity to intestinal inflammation and increased TNFαexpression. In addition, the lack of RAGE seemed to lower age-related TNFα increase in a healthy rodent model. Itprovides a potential avenue for future research to delve into understanding the influence of dAGEs on the onset ofdifferent diseases and health conditions.